Diffuse Pontine Glioma

Most children with DPG have evidence of cerebellar dysfunction (87%), multiple lower cranial nerve palsies (77%), and motor paresis and sensory changes secondary to long-tract involvement (53%).⁵ The presence of this classic triad almost always makes the diagnosis on a clinical basis alone.

The extent and duration of symptoms are usually less than expected given the size of the tumor on imaging studies and the involved brainstem structures. The duration of symptoms is relatively short, and 94% of patients will have had symptoms for less than 6 months at time of initial evaluation. The duration of symptoms is a predictor of outcome, with a better outcome if symptoms were present for 6 months or longer and a significantly worse outcome for tumors with symptoms lasting 1 month or less.⁵

DPGs most commonly affect the lower cranial nerves (VI, VII, IX, and X), and most children will have diplopia. The presence of an isolated cranial nerve palsy of longer duration (usually cranial nerve VII) is associated with a slightly better outcome and longer survival. Other clinical signs are related to involvement of the cerebellar peduncles and result in ataxia, which can be truncal or appendicular. Involvement of the long tracts/cerebral peduncles leads to hemiparesis but rarely sensory changes.

Although the tumor mass is usually centered in the pons and is large when initially evaluated, obstruction of the fourth ventricle is rare and hydrocephalus is seen in only about 20% of patients at the time of diagnosis. However, hydrocephalus is frequently seen at time of tumor progression and may require separate treatment in addition to the tumor-directed therapy.

Tectal Glioma

Tectal gliomas are considered a subgroup of focal BSGs and are most often initially manifested as hydrocephalus secondary to aqueductal stenosis.^6–8 Despite involvement of the quadrigeminal plate, the classic Parinaud syndrome is not as commonly seen with these tumors as with pineal tumors causing compression on this structure. Most patients have had a long-standing history of headaches and on occasion “clumsiness” or ataxia, and imaging studies are usually obtained in the course of investigation of the headaches, thus establishing the diagnosis. Tectal lesions may in rare cases be accompanied by oculomotor palsy.⁶ Many patients will have macrocephaly on examination, in addition to the other neurological findings. Rapidly progressive symptoms should raise concern about the biologic behavior and pathology of these tumors. Atypical or more aggressive tectal gliomas tend to occur in younger patients.⁹

Focal Tumors

Focal tumors can arise anywhere in the brainstem and cause symptoms that reflect the involved anatomic structures. Midbrain lesions are commonly manifested as hydrocephalus and focal neurological deficits, depending on the location of the tumor. Focal pontine lesions are characterized by isolated facial palsies, long-tract signs, or hearing loss. Lesions in the medulla oblongata involve the lower cranial nerves and can cause respiratory difficulties (including apnea), recurrent upper respiratory tract infections and pneumonia, and swallowing difficulties with aspiration of food and saliva. In infants, failure to thrive may be the initial symptom. The gag reflex may be affected, and tongue asymmetry might be present.¹⁰

Exophytic Tumors

These tumors differ from the other subgroups of BSGs in that they are the only BSG originating from the subependymal glia in the floor of the fourth ventricle and growing posteriorly, thereby filling the fourth ventricle.¹¹ Only about 10% of the tumor mass growth occurs in the brainstem, which is spared for a long time and thus results in very gradually progressive symptoms. Careful history taking commonly reveals that the initial symptoms have been present for longer than 1 year.¹² Obstruction of cerebrospinal fluid (CSF) pathways in the fourth ventricle is not uncommon and leads to intractable vomiting and failure to thrive in infants and headaches, vomiting, and ataxia in older children. Papilledema and torticollis are frequently present on examination and indicate increased intracranial pressure and chronic tonsillar herniation.¹²

Cervicomedullary Tumors

Two clinical syndromes may be distinguished, depending on the location of these tumors at the junction between the medulla and cervical spinal cord.

Tumors arising in the medulla typically cause symptoms of lower cranial nerve dysfunction, including failure to thrive, dysphagia, dysarthria and dysphonia, chronic upper respiratory tract infections and aspiration, and sleep apnea. Lesions stemming from the cervical spinal cord are usually manifested as neck pain, torticollis, and sensorimotor deficits in the limbs or cervical myelopathy. Cranial nerve palsies are not typically encountered, and hydrocephalus is present when the bulk of the tumor obstructs the fourth ventricle outlets.

The average duration of symptoms is 2.1 years because of the slowly progressive and low-grade nature of the lesions.^4,13,14

Computed Tomography

Computed tomography (CT) is useful as a screening tool for the presence of a tumor or hydrocephalus, or both, but it cannot delineate the exact location and extent of brainstem tumors. Patients with DPG have diffuse enlargement of the pons and posterior displacement of the fourth ventricle but rarely hydrocephalus. Contrast-enhanced images show nonhomogeneous enhancement patterns and occasionally ring enhancement.

Focal tumors in the midbrain and tectum can be missed on CT, which may lead to a false-negative diagnosis and suspicion for late-onset aqueductal stenosis.

CT can show the rare presence of calcifications in brainstem tumors better than MRI can. If present, this usually implies an atypical BSG rather than a DPG.¹⁵

Single-photon emission CT using thallium 201 shows accumulation of the radioactive tracer in the tumor, which is 90% specific for a BSG but is not correlated with tumor grade, enhancement patterns of other contrast media, or necrosis.¹⁶

Magnetic Resonance Imaging

MRI is the preferred method for imaging brainstem tumors. DPGs are generally hypointense on T1-weighted sequences with diffuse enlargement of the pons and indistinct margins. T1-weighted images tend to underestimate the true extent of the tumor, which is best appreciated on T2-weighted images and is hyperintense on these sequences. The tumors characteristically engulf the basilar artery ventrally. Contrast enhancement is variable and may be nonhomogeneous inside or around the tumor or may be absent altogether in about a third of patients,¹⁵ so it is of limited prognostic value (Fig. 203-1).¹⁷ Dissemination along the CSF pathways is rare, although it can be seen at diagnosis in about 15% of cases, and therefore it is imperative that the entire CNS axis be imaged at time of initial diagnosis.

FIGURE 203-1 Magnetic resonance imaging of diffuse pontine glioma (DPG). A, Sagittal T1-weighted imaging showing diffuse enlargement of the pons. B, Sagittal T2-weighted appearance of DPG. C, Axial fluid-attenuated inversion recovery sequences showing tumor engulfing the basilar artery ventrally. D, T1-weighted contrast-enhanced imaging demonstrating irregular enhancement within the tumor.

Focal lesions appear to be better circumscribed and are generally isointense on T1-weighted sequences and brightly enhancing. They occupy less than 50% of a brainstem region, thus leading to the designation “focal.” Focal tumors are more common in the midbrain and medulla and least common in the pons; they are usually well delineated without a large amount of edema or evidence of focal infiltration (Fig. 203-2).^2,17

FIGURE 203-2 Focal pontine juvenile pilocytic astrocytoma. A, Axial T1-weighted contrast-enhanced image showing a well-circumscribed tumor with cysts. B, Sagittal T1-weighted image showing a focal lesion in the pons. C and D, Axial and sagittal T1-weighted contrast-enhanced images showing complete resection of the tumor and no recurrence 5 years later.

Tectal tumors are infiltrating lesions in the tectal plate that are poorly delineated and rarely enhance. They are usually hypointense on T1-weighted images and bright on T2-weighted sequences (Fig. 203-3). Size larger than 2 cm and enhancement are features associated with a worse outcome and suggest an atypical tectal tumor.¹⁸

FIGURE 203-3 Tectal glioma. A, Sagittal T2-weighted imaging demonstrating the tumor with expansion of the tectum and hydrocephalus. B, Axial fluid-attenuated inversion recovery imaging showing the infiltrative nature of the tumor.

Dorsal exophytic tumors are not usually well delineated from the underlying brainstem and frequently extend into the fourth ventricle. They have variable enhancement and follow the imaging characteristics of infiltrating gliomas.

CMJ tumors are similar in appearance to infiltrating gliomas, with evidence of growth in the medulla and cervical spinal cord. The epicenter is usually at the foramen magnum area, and there is frequently a large exophytic component that is either obstructing the outlet of the fourth ventricle or located in the cerebellopontine angle and causing compression and distortion of the lower medulla (Fig. 203-4).

FIGURE 203-4 Dorsal exophytic and cervicomedullary junction (CMJ) tumors. A and B, Sagittal and axial T1-weighted contrast-enhanced images of a dorsal exophytic tumor in an 18-month-old boy with failure to thrive. C, Axial T1-weighted image of the CMJ tumor demonstrating a rim of normal tissue around the tumor. D, T1-weighted contrast-enhanced image showing irregular enhancement within the tumor.

Magnetic resonance spectroscopy in patients with BSG has shown lower N-acetylaspartate levels than in normal controls, which may be helpful in distinguishing them from the benign diffuse pontine enlargements seen in patients with neurofibromatosis type 1 (NF1) or acute demyelinating encephalomyelitis.^19,20 Lesions associated with NF1 tend to be multifocal, frequently also extend into the cerebellar peduncles, and may show contrast enhancement.²¹

Fluorodeoxyglucose positron emission tomography has been used to differentiate between low-grade and high-grade lesions and also to evaluate response to treatment. Diffusion tensor imaging has recently been introduced in an attempt to identify involvement of white matter tracts by the tumor and potentially aid in the surgical management of these tumors.²²

Differential Diagnosis

Most diffuse lesions in the pediatric population are fibrillary infiltrating gliomas, but the histologic grade can vary considerably between low grade (37%), anaplastic (56%), and glioblastoma (5%).⁵ The true incidences are not known because of the low biopsy and resection rate of these tumors. Other pathologies include pilocytic astrocytoma, infantile ganglioglioma, ganglioglioma and gangliocytoma, primitive neuroectodermal tumor, and atypical teratoid-rhabdoid tumor.

Vascular anomalies can also be seen and include the rare cavernous or arteriovenous malformations. Hemangioblastomas and lesions associated with NF1 should also be included in the differential diagnosis but generally have a characteristic radiographic appearance.

In countries other than the United States, the relative incidence of tuberculomas, abscesses, and focal inflammatory and demyelinating lesions may be higher and should be taken into account. The patient’s signs, symptoms, and history in these cases are likely to be different from those of a patient with a BSG.

Fibrillary Astrocytoma

Most BSGs are diffuse fibrillary astrocytomas. However, grading is difficult because of the issue of sampling and the relative rarity of specimens available for pathologic examination. They are predominantly composed of fibrillary neoplastic astrocytes with nuclear atypia. Mitotic activity (Ki-67/MIB-1 labeling index) is usually less than 4%, and necrosis and microvascular proliferation can be present. Molecular characterization commonly shows TP53 mutations (>60%), although they are not a predictor of outcome, loss of heterozygosity of 22q (in about a third), and less often a number of other chromosomal abnormalities.²⁷

The cytogenetic abnormalities of diffuse BSGs resemble those of adult malignant gliomas, including TP53 mutations and mutated epidermal growth factor receptor genes. In a study of six patients, 50% had multiple abnormalities and progressed rapidly.²⁸ ERBB1 was found to be overexpressed in some DPGs, and the grade of amplification correlated with the grade of the tumor.²⁹